Wang Benfan, Wu H Helena, Abuetabh Yasser, Leng Sarah, Davidge Sandra T, Flores Elsa R, Eisenstat David D, Leng Roger
Department of Laboratory Medicine and Pathology, 370 Heritage Medical Research Center, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
Department of Obstetrics & Gynecology & Physiology, 232 Heritage Medical Research Center, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
Cell Death Dis. 2022 Apr 22;13(4):397. doi: 10.1038/s41419-022-04854-1.
As a key component of the RNA-induced silencing complex (RISC), Argonaute2 (Ago2) exhibits a dual function regulatory role in tumor progression. However, the mechanistic basis of differential regulation remains elusive. p63 is a homolog of the tumor suppressor p53. p63 isoforms play a critical role in tumorigenesis and metastasis. Herein, we show that p63 isoforms physically interact with and stabilize Ago2. Expression of p63 isoforms increases the levels of Ago2 protein, while depletion of p63 isoforms by shRNA decreases Ago2 protein levels. p63 strongly guides Ago2 dual functions in vitro and in vivo. Ectopic expression of the miR-144/451 cluster increases p63 protein levels; TAp63 transactivates the miR-144/451 cluster, forming a positive feedback loop. Notably, miR-144 activates p63 by directly targeting Itch, an E3 ligase of p63. Ectopic expression of miR-144 induces apoptosis in H1299 cells. miR-144 enhances TAp63 tumor suppressor function and inhibits cell invasion. Our findings uncover a novel function of p63 linking the miRNA-144 cluster and the Ago2 pathway. FACTS AND QUESTIONS: Identification of Ago2 as a p63 target. Ago2 exhibits a dual function regulatory role in tumor progression; however, the molecular mechanism of Ago2 regulation remains unknown. p63 strongly guides Ago2 dual functions in vitro and in vivo. Unraveling a novel function of p63 links the miRNA-144 cluster and the Ago2 pathway.
作为RNA诱导沉默复合体（RISC）的关键组成部分，Argonaute2（Ago2）在肿瘤进展中发挥双重功能调节作用。然而，差异调节的机制基础仍不清楚。p63是肿瘤抑制因子p53的同源物。p63异构体在肿瘤发生和转移中起关键作用。在此，我们表明p63异构体与Ago2发生物理相互作用并使其稳定。p63异构体的表达增加了Ago2蛋白水平，而通过短发夹RNA（shRNA）耗尽p63异构体则降低了Ago2蛋白水平。p63在体外和体内强烈引导Ago2的双重功能。miR-144/451簇的异位表达增加了p63蛋白水平；TAp63反式激活miR-144/451簇，形成正反馈环。值得注意的是，miR-144通过直接靶向p63的E3连接酶Itch来激活p63。miR-144的异位表达诱导H1299细胞凋亡。miR-144增强TAp63的肿瘤抑制功能并抑制细胞侵袭。我们的研究结果揭示了p63连接miRNA-144簇和Ago2途径的新功能。事实与问题：鉴定Ago2为p63靶点。Ago2在肿瘤进展中发挥双重功能调节作用；然而，Ago2调节的分子机制仍然未知。p63在体外和体内强烈引导Ago2的双重功能。揭示p63的新功能连接了miRNA-144簇和Ago2途径。
